chrX-49030447-C-G

Position:

• chrX-49030447-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006521.6(TFE3):​c.1439G>C​(p.Gly480Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,209,577 control chromosomes in the GnomAD database, including 2 homozygotes. There are 394 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., 16 hem., cov: 22)
  • Exomes 𝑓: 0.0010 (2 hom. 378 hem.)
• Consequence: TFE3 NM_006521.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.50

Genes affected

TFE3 (HGNC:11752): (transcription factor binding to IGHM enhancer 3) This gene encodes a basic helix-loop-helix domain-containing transcription factor that binds MUE3-type E-box sequences in the promoter of genes. The encoded protein promotes the expression of genes downstream of transforming growth factor beta (TGF-beta) signaling. This gene may be involved in chromosomal translocations in renal cell carcinomas and other cancers, resulting in the production of fusion proteins. Translocation partners include PRCC (papillary renal cell carcinoma), NONO (non-POU domain containing, octamer-binding), and ASPSCR1 (alveolar soft part sarcoma chromosome region, candidate 1), among other genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009028733).
• BP6: Variant X-49030447-C-G is Benign according to our data. Variant chrX-49030447-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 723210.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-49030447-C-G is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFE3	NM_006521.6	c.1439G>C	p.Gly480Ala	missense_variant	10/10	ENST00000315869.8	NP_006512.2
TFE3	NM_001282142.2	c.1124G>C	p.Gly375Ala	missense_variant	10/10		NP_001269071.1
TFE3	XM_024452432.2	c.*69G>C		3_prime_UTR_variant	11/11		XP_024308200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFE3	ENST00000315869.8	c.1439G>C	p.Gly480Ala	missense_variant	10/10	1	NM_006521.6	ENSP00000314129.7
TFE3	ENST00000493583.5	n.*1044G>C		non_coding_transcript_exon_variant	10/10	2		ENSP00000476976.1
TFE3	ENST00000493583.5	n.*1044G>C		3_prime_UTR_variant	10/10	2		ENSP00000476976.1

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 71 AN: 111289 Hom.: 0 Cov.: 22 AF XY: 0.000478 AC XY: 16 AN XY: 33479

Gnomad AFR AF: 0.000523

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000575

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00114

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.000331

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000774

Gnomad OTH AF: 0.000671

GnomAD3 exomes AF: 0.000818 AC: 149 AN: 182112 Hom.: 1 AF XY: 0.000847 AC XY: 57 AN XY: 67316

Gnomad AFR exome AF: 0.000608

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.000577

Gnomad SAS exome AF: 0.000943

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000943

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.00101 AC: 1113 AN: 1098236 Hom.: 2 Cov.: 37 AF XY: 0.00104 AC XY: 378 AN XY: 363604

Gnomad4 AFR exome AF: 0.000682

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.000258

Gnomad4 EAS exome AF: 0.000430

Gnomad4 SAS exome AF: 0.000960

Gnomad4 FIN exome AF: 0.000148

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000638 AC: 71 AN: 111341 Hom.: 0 Cov.: 22 AF XY: 0.000477 AC XY: 16 AN XY: 33541

Gnomad4 AFR AF: 0.000522

Gnomad4 AMR AF: 0.000574

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00114

Gnomad4 SAS AF: 0.000371

Gnomad4 FIN AF: 0.000331

Gnomad4 NFE AF: 0.000775

Gnomad4 OTH AF: 0.000662

Alfa AF: 0.000509 Hom.: 3

Bravo AF: 0.000748

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.00119 AC: 8

ExAC AF: 0.00102 AC: 124

EpiCase AF: 0.00120

EpiControl AF: 0.000830

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.92	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.018
DANN	Benign	0.32
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.20	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.039
Sift	Benign	0.33	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.058
MVP		0.082
MPC		0.035
ClinPred		0.0071	T
GERP RS		-7.9
Varity_R		0.041
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149649619; hg19: chrX-48887958; COSMIC: COSV100252919; COSMIC: COSV100252919;